STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression

Abstract

Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) on macrophages induces a robust pro-inflammatory response that is dependent on metabolic reprogramming. These innate metabolic changes have been compared to aerobic glycolysis in tumour cells. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming are unknown. Here we show that TLR4 activation induces a signalling cascade recruiting TRAF6 and TBK-1, while TBK-1 phosphorylates STAT3 on S727. Using a genetically engineered mouse model incapable of undergoing STAT3 Ser727 phosphorylation, we show ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, production of the central immune response metabolite succinate and inflammatory cytokine production in a model of LPS-induced inflammation. Our study identifies non-canonical STAT3 activation as the crucial signalling intermediary for TLR4-induced glycolysis, macrophage metabolic reprogramming and inflammation.

References 42

1. 1.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

2. 2.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

3. 3.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

4. 4.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

5. 5.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

6. 6.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

7. 7.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

8. 8.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

9. 9.

   This reference’s wording can’t be shown under the paper’s licence.

   Not in our library

10. 10.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

11. 11.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

12. 12.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

13. 13.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

14. 14.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

15. 15.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

16. 16.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

17. 17.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

18. 18.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

19. 19.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

20. 20.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

21. 21.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

22. 22.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

23. 23.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

24. 24.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

25. 25.
    Characterization of murine macrophages from bone marrow, spleen and peritoneum · 2013

    No notice
26. 26.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

27. 27.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

28. 28.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

29. 29.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

30. 30.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

31. 31.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

32. 32.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

33. 33.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

34. 34.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

35. 35.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

36. 36.
    Interleukin-1 receptor–associated kinase 4 (IRAK4) plays a dual role in myddosome formation and Toll-like receptor signaling · 2018

    No notice
37. 37.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

38. 38.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

39. 39.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

40. 40.

    This reference’s wording can’t be shown under the paper’s licence.

    Not in our library

Cited by papers we hold 5

• Harnessing innate immune pathways for therapeutic advancement in cancer · 2024
  No notice
• Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation · 2022
  No notice
• Major pathways involved in macrophage polarization in cancer · 2022
  No notice
• Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice · 2021
  Not checked
• Donepezil Regulates LPS and Aβ-Stimulated Neuroinflammation through MAPK/NLRP3 Inflammasome/STAT3 Signaling · 2021
  No notice

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